Objectives are to understand the mechanisms involved in the control of the magnocellular neuroendocrine system. Ubiquitous among mammalian species, this system is largely responsible for the manufacture and distribution of the peptides oxytocin and vasopressin which have well-known actions on peripheral tissues (e.g. mammary glands, uterine and vascular smooth muscle, kidneys and others). These peptides have also been found at central synapses, broadening their functional role to include neuro- transmitter /modulator as well as neuroendocrine actions. That the opioid peptide dynorphin is co-localized and co-released with vasopressin has enhanced interest in factors controlling the activity of these neurons. In this application, special attention is paid to the major hypothalamic nuclei, the supra- optic (SON) and paraventricular (PVN) nuclei, that chiefly comprise the magnocellular system. Work over the past five years of support has focused on synaptic inputs and non-synaptic mechanisms, cell-cell interactions and local circuits that appear to be involved in controlling excitability, activation and inactivation of this system under a variety of physiological conditions. This approach will be continued during the period of requested support, since this model system displays a truly remarkable degree of plasticity, depending upon specific physiological demands. Specific aims for the requested period of support are: 1. To investigate mechanisms involved in modulation of electrical coupling among magnocellular neuropeptidergic neurons. 2. To further characterize the direct synaptic inputs to these neuron from olfactory bulbs (excitatory amino acid-mediated) and tuberomammillary nuclei (histaminergic). 3. To investigate the roles of nearby local circuit neurons (e.g. medial amygdaloid, perinuclear zone) in the control of the SON magnocellular neurons. 4. To investigate the influences on neuronal excitability of physiological state-related variables, such as gonadal steroids and osmotic pressure. The methodology to be used in this work includes: (a) intracellular recording and staining of neurons in brain slices maintained in vitro, (b) immunocytochemical identification of recorded and injected cells, (c) application of transmitter/modulator agonists and antagonists, (d) manipulations of the hydrational and reproductive hormonal states of rats.